It becomes more apparent that the pathogenesis of HIV-1 infection is complex and multifactorial. There is little doubt that host immune response to HIV-1 infection plays a key role in determining the fate of disease progression. However, emerging data also point to a critical role of HIV-1 itself in the disease progression. Over the past few years, we have obtained some promising results that viral load, viral genetic diversity, and phenotype of viruses during the first year of HIV-1 infection correlate with subsequent disease progression. In this application, we will continue to study the relationship between viral load, viral genetic diversity, and phenotype of viruses and disease progression in IDUs. In particular, we propose to test the hypothesis that viral markers early after HIV-1 infection (within the first year of seroconversion) have prognostic value for subsequent disease progression. To substantiate our preliminary finding, we will (1). To study the relationship between plasma viral RNA load during the first year of primary infection and subsequent CD4 cell decline and progression to AIDS; (2). To determine the relationship of genetic diversity of HIV-1 variants during the first year of primary infection and subsequent CD4 cell decline and disease progression (AIDS); (3). To identify the prevalence of dual-tropic or T-tropic HIV-1 variants in rapid progressors vs. slow progressors during the first year of primary infection and to study the relationship of viral phenotype and CD8+ and CD4+ T cell decline and AIDS development. These studies will provide information that should prove useful in characterizing differences in HIV pathogenesis in IDUs, and should provide useful information for future comparison between IDUs and individuals who acquire HIV infection as a result of sexual transmission. They should also provide information that may prove critical for the development of candidate preventive and therapeutic strategies.